Psychiatry - Research Publications

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    Mixed Methods Thematic Analysis of a Randomised Controlled Trial of Adjunctive Mitochondrial Agents for Bipolar Depression
    Russell, SE ; Wrobel, AL ; Dean, OM ; Berk, M ; Dodd, S ; Ng, CH ; Malhi, GS ; Cotton, SM ; Sarris, J ; Turner, A (KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2022-05-01)
    Objective: There is often a shortfall in recovery following treatment for an episode of bipolar disorder (BD). Exploration of participant's experience provides vital information to enhance statistical outcomes for novel therapy trials. This study used mixed-methods to explore participants' experience of a trial testing N -acetyl cysteine (NAC) and mitochondrially active nutraceuticals for BD depression. Methods: Case: report forms from a randomised controlled trial (RCT) of BD depression (n = 148) were analysed using a pragmatic adaption of grounded theory and thematic analysis. Results: Thematic analysis of 148 study participants indicated numerous changes in participant experience over time. For example, perceived environmental stressors reported by participants decreased over the trial in both treatment groups. Quantitative analysis of the themes revealed more positive theme reports in the combination treatment arm compared to the placebo arm and there were more negative themes identified in the placebo arm, compared to the NAC arm. Conclusion: This approach revealed additional results not elucidated in the primary quantitative analysis. This emphasises the value of mixed-methods research in capturing participants' experiences in RCTs and detecting possible latent benefits and risks. Such methods can detect latent target signals in novel therapy trials conducted in BD and generate novel hypotheses.
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    Trajectories of depressive symptoms in older adults and associated health outcomes
    Agustini, B ; Lotfaliany, M ; Mohebbi, M ; Woods, RL ; McNeil, JJ ; Nelson, MR ; Shah, RC ; Murray, AM ; Reid, CM ; Tonkin, A ; Ryan, J ; Williams, LJ ; Forbes, MP ; Berk, M (Springer Science and Business Media LLC, 2022-04-01)
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    N-acetyl cysteine (NAC) augmentation in the treatment of obsessive-compulsive disorder: A phase III, 20-week, double-blind, randomized, placebo-controlled trial.
    Sarris, J ; Byrne, G ; Castle, D ; Bousman, C ; Oliver, G ; Cribb, L ; Blair-West, S ; Brakoulias, V ; Camfield, D ; Ee, C ; Chamoli, S ; Boschen, M ; Dean, OM ; Dowling, N ; Menon, R ; Murphy, J ; Metri, N-J ; Nguyen, TP ; Wong, A ; Jordan, R ; Karamacoska, D ; Rossell, SL ; Berk, M ; Ng, CH (Elsevier BV, 2022-07-13)
    OBJECTIVE: Preliminary evidence has suggested that adjunctive N-acetylcysteine (NAC), an antioxidant precursor to glutathione, may reduce symptoms of obsessive-compulsive disorder (OCD). We conducted a 20-week, multi-site, randomized controlled trial to investigate the safety and efficacy of the adjunctive use of NAC in OCD. METHODS: The study was a phase III, 20-week, double-blind, randomized controlled trial across multiple sites in Australia investigating 2 g to 4 g per day of NAC (titrated according to response) in 98 participants with DSM-5 diagnosed OCD. Data were analysed using linear mixed effects models for the 89 participants who attended at least one follow-up visit. RESULTS: A modified intention-to-treat analysis of the primary outcome found no evidence that NAC reduced symptoms of OCD measured on the Yale-Brown Obsessive-Compulsive Scale, relative to placebo (mean difference at week 20 = 0.53, 95% compatibility interval = -2.18, 3.23; p = 0.70; favouring placebo). There was also no evidence that NAC, compared to placebo, improved outcomes on the secondary measures including anxiety, depression, quality of life, functioning, or clinician/participant impression. NAC was well-tolerated with only mild gastrointestinal adverse events associated with the treatment. CONCLUSION: We found no evidence supporting the efficacy of the adjunctive use of NAC in OCD.
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    Strategies and foundations for scientific discovery in longitudinal studies of bipolar disorder
    McInnis, MG ; Andreassen, OA ; Andreazza, AC ; Alon, U ; Berk, M ; Brister, T ; Burdick, KE ; Cui, D ; Frye, M ; Leboyer, M ; Mitchell, PB ; Merikangas, K ; Nierenberg, AA ; Nurnberger, J ; Pham, D ; Vieta, E ; Yatham, LN ; Young, AH (WILEY, 2022-03-18)
    Bipolar disorder (BD) is a complex and dynamic condition with a typical onset in late adolescence or early adulthood followed by an episodic course with intervening periods of subthreshold symptoms or euthymia. It is complicated by the accumulation of comorbid medical and psychiatric disorders. The etiology of BD remains unknown and no reliable biological markers have yet been identified. This is likely due to lack of comprehensive ontological framework and, most importantly, the fact that most studies have been based on small nonrepresentative clinical samples with cross-sectional designs. We propose to establish large, global longitudinal cohorts of BD studied consistently in a multidimensional and multidisciplinary manner to determine etiology and help improve treatment. Herein we propose collection of a broad range of data that reflect the heterogenic phenotypic manifestations of BD that include dimensional and categorical measures of mood, neurocognitive, personality, behavior, sleep and circadian, life-story, and outcomes domains. In combination with genetic and biological information such an approach promotes the integrating and harmonizing of data within and across current ontology systems while supporting a paradigm shift that will facilitate discovery and become the basis for novel hypotheses.
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    Mindfulness-Based Online Intervention to Improve Quality of Life in Late-Stage Bipolar Disorder: A Randomized Clinical Trial
    Murray, G ; Thomas, N ; Michalak, EE ; Jones, SH ; Lapsley, S ; Bowe, SJ ; Foley, F ; Fletcher, K ; Perich, T ; Johnson, SL ; Cotton, S ; Berk, L ; Mihalopoulos, C ; Kyrios, M ; Berk, M (AMER PSYCHOLOGICAL ASSOC, 2021-10-01)
    Objective: Adjunctive psychological interventions improve outcomes in bipolar disorder (BD), but people in latter stages likely have different clinical needs. The objective here was to test the hypothesis that for people with ≥10 episodes of BD, a brief online mindfulness-based intervention (ORBIT 2.0) improves quality of life (QoL) relative to a Psychoeducation control. Method: A rater-masked, pragmatic superiority randomized clinical trial compared ORBIT 2.0 with active control. Both interventions were 5-week coach-supported programs with treatment as usual continued. Inclusion criteria included age 18-65 years, confirmed diagnosis of BD, and history of ≥10 episodes. Measures were collected at baseline, postintervention, and 3- and 6-month follow-ups. The main outcome was QoL, measured on the Brief Quality of Life in Bipolar Disorder (Brief QoL.BD) at 5 weeks, using intention-to-treat analyses. Results: Among N = 302 randomized participants, the primary hypothesis was not supported (Treatment × Time β = -0.69, 95% CI [-2.69, 1.31], p = .50). The main effect of Time was not significant in either condition, indicating no improvement in either group. Recruitment was feasible, the platform was safe, both interventions were highly acceptable, but usage was suboptimal. Post hoc analyses found both interventions effective for participants not in remission from depression at baseline. Conclusions: In people with late-stage BD, an online mindfulness-based intervention was not superior to psychoeducational control in improving QoL. Online delivery was found to be safe and acceptable. Future interventions may need to be higher intensity, address engagement challenges, and target more symptomatic individuals. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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    Universal depression prevention: An umbrella review of meta-analyses
    Hoare, E ; Collins, S ; Marx, W ; Callaly, E ; Moxham-Smith, R ; Cuijpers, P ; Holte, A ; Nierenberg, AA ; Reavley, N ; Christensen, H ; Reynolds, CF ; Carvalho, AF ; Jacka, F ; Berk, M (PERGAMON-ELSEVIER SCIENCE LTD, 2021-11-09)
    Depression is a disabling, highly prevalent, frequently chronic, and difficult-to-treat disorder with an immense cognitive, social, and economic burden. Given that many of the advances in other non-communicable disorders like cancer have been in prevention rather than treatment, the prevention of depression is currently an unmet public health priority. We sought to provide an overview of the meta-analytic literature through conducting a systematic umbrella review of universally delivered preventive interventions for depression. The search was conducted on March 18, 2021 utilising the following databases (all accessed through EBSCOHost); Allied and Complementary Medicine Database, CINAHL Complete, Global Health, Health Source: Nursing/Academic Edition, MEDLINE Complete and APA PsychArticles. The following search terms related to depression, prevention, and trial study design. Two authors independently screened articles and a third resolved discrepancies. Eligibility criteria sought to identify meta-analyses that investigated the prevention of depression (i.e., reduced incidence) through intervention studies that were universal, in that they were designed to be delivered to entire populations Six meta-analyses on psychological interventions, two school-based meta-analyses, and one eHealth meta-analysis were included in this umbrella review. Findings indicated that all identified studies were of good quality and one was of fair quality. One previous meta-review that examined physical activity to prevent depression was included in results, comprising eight meta-analyses. Preventive interventions have primarily and successfully utilized psychological therapeutic components, delivered at the school, community, and workplace settings. Both school- and eHealth-based interventions hold some utility for depression prevention. There is meta-analytic evidence that physical activity is efficacious for depression prevention. However, universal prevention is inconsistently defined. There is a pressing need for well-designed randomized controlled preventative interventions for depression before recommendations can be universally accepted with convincing level of evidence.
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    Gender, age at onset, and duration of being ill as predictors for the long-term course and outcome of schizophrenia: an international multicenter study
    Fountoulakis, KN ; Dragioti, E ; Theofilidis, AT ; Wiklund, T ; Atmatzidis, X ; Nimatoudis, I ; Thys, E ; Wampers, M ; Hranov, L ; Hristova, T ; Aptalidis, D ; Milev, R ; Iftene, F ; Spaniel, F ; Knytl, P ; Furstova, P ; From, T ; Karlsson, H ; Walta, M ; Salokangas, RKR ; Azorin, J-M ; Bouniard, J ; Montant, J ; Juckel, G ; Haussleiter, IS ; Douzenis, A ; Michopoulos, I ; Ferentinos, P ; Smyrnis, N ; Mantonakis, L ; Nemes, Z ; Gonda, X ; Vajda, D ; Juhasz, A ; Shrivastava, A ; Waddington, J ; Pompili, M ; Comparelli, A ; Corigliano, V ; Rancans, E ; Navickas, A ; Hilbig, J ; Bukelskis, L ; Stevovic, LI ; Vodopic, S ; Esan, O ; Oladele, O ; Osunbote, C ; Rybakowski, JK ; Wojciak, P ; Domowicz, K ; Figueira, ML ; Linhares, L ; Crawford, J ; Panfil, A-L ; Smirnova, D ; Izmailova, O ; Lecic-Tosevski, D ; Temmingh, H ; Howells, F ; Bobes, J ; Garcia-Portilla, MP ; Garcia-Alvarez, L ; Erzin, G ; Karadag, H ; De Sousa, A ; Bendre, A ; Hoschl, C ; Bredicean, C ; Papava, I ; Vukovic, O ; Pejuskovic, B ; Russell, V ; Athanasiadis, L ; Konsta, A ; Fountoulakis, NK ; Stein, D ; Berk, M ; Dean, O ; Tandon, R ; Kasper, S ; De Hert, M (CAMBRIDGE UNIV PRESS, 2021-08-09)
    BACKGROUND: The aim of the current study was to explore the effect of gender, age at onset, and duration on the long-term course of schizophrenia. METHODS: Twenty-nine centers from 25 countries representing all continents participated in the study that included 2358 patients aged 37.21 ± 11.87 years with a DSM-IV or DSM-5 diagnosis of schizophrenia; the Positive and Negative Syndrome Scale as well as relevant clinicodemographic data were gathered. Analysis of variance and analysis of covariance were used, and the methodology corrected for the presence of potentially confounding effects. RESULTS: There was a 3-year later age at onset for females (P < .001) and lower rates of negative symptoms (P < .01) and higher depression/anxiety measures (P < .05) at some stages. The age at onset manifested a distribution with a single peak for both genders with a tendency of patients with younger onset having slower advancement through illness stages (P = .001). No significant effects were found concerning duration of illness. DISCUSSION: Our results confirmed a later onset and a possibly more benign course and outcome in females. Age at onset manifested a single peak in both genders, and surprisingly, earlier onset was related to a slower progression of the illness. No effect of duration has been detected. These results are partially in accord with the literature, but they also differ as a consequence of the different starting point of our methodology (a novel staging model), which in our opinion precluded the impact of confounding effects. Future research should focus on the therapeutic policy and implications of these results in more representative samples.
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    Lithium therapy and weight change in people with bipolar disorder: A systematic review and meta-analysis.
    Gomes-da-Costa, S ; Marx, W ; Corponi, F ; Anmella, G ; Murru, A ; Pons-Cabrera, MT ; Giménez-Palomo, A ; Gutiérrez-Arango, F ; Llach, CD ; Fico, G ; Kotzalidis, GD ; Verdolini, N ; Valentí, M ; Berk, M ; Vieta, E ; Pacchiarotti, I (Elsevier BV, 2022-03)
    Lithium remains the gold standard maintenance treatment for Bipolar Disorder (BD). However, weight gain is a side effect of increasing relevance due to its metabolic implications. We conducted a systematic review and meta-analysis aimed at summarizing evidence on the use of lithium and weight change in BD. We followed the PRISMA methodology, searching Pubmed, Scopus and Web of Science. From 1003 screened references, 20 studies were included in the systematic review and 9 included in the meta-analysis. In line with the studies included in the systematic review, the meta-analysis revealed that weight gain with lithium was not significant, noting a weight increase of 0.462 Kg (p = 0158). A shorter duration of treatment was significantly associated with more weight gain. Compared to placebo, there were no significant differences in weight gain. Weight gain was significantly lower with lithium than with active comparators. This work reveals a low impact of lithium on weight change, especially compared to some of the most widely used active comparators. Our results could impact clinical decisions.
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    Treatment of refractory obsessive-compulsive disorder with nutraceuticals (TRON): a 20-week, open label pilot study
    Sarris, J ; Byrne, GJ ; Oliver, G ; Cribb, L ; Blair-West, S ; Castle, D ; Dean, OM ; Camfield, DA ; Brakoulias, V ; Bousman, C ; Dowling, N ; Ee, C ; Murphy, J ; Menon, R ; Berk, M ; Chamoli, S ; Boschen, M ; Ng, CH (CAMBRIDGE UNIV PRESS, 2021-06-21)
    BACKGROUND: Obsessive-compulsive disorder (OCD) is often challenging to treat and resistant to psychological interventions and prescribed medications. The adjunctive use of nutraceuticals with potential neuromodulatory effects on underpinning pathways such as the glutamatergic and serotonergic systems is one novel approach. OBJECTIVE: To assess the effectiveness and safety of a purpose-formulated combination of nutraceuticals in treating OCD: N-acetyl cysteine, L-theanine, zinc, magnesium, pyridoxal-5' phosphate, and selenium. METHODS: A 20-week open label proof-of-concept study was undertaken involving 28 participants with treatment-resistant DSM-5-diagnosed OCD, during 2017 to 2020. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale (YBOCS), administered every 4 weeks. RESULTS: An intention-to-treat analysis revealed an estimated mean reduction across time (baseline to week-20) on the YBOCS total score of -7.13 (95% confidence interval = -9.24, -5.01), with a mean reduction of -1.21 points per post-baseline visit (P ≤ .001). At 20-weeks, 23% of the participants were considered "responders" (YBOCS ≥35% reduction and "very much" or "much improved" on the Clinical Global Impression-Improvement scale). Statistically significant improvements were also revealed on all secondary outcomes (eg, mood, anxiety, and quality of life). Notably, treatment response on OCD outcome scales (eg, YBOCS) was greatest in those with lower baseline symptom levels, while response was limited in those with relatively more severe OCD. CONCLUSIONS: While this pilot study lacks placebo-control, the significant time effect in this treatment-resistant OCD population is encouraging and suggests potential utility especially for those with lower symptom levels. Our findings need to be confirmed or refuted via a follow-up placebo-controlled study.